AR074965A1 - BRIDGED AND FUSED HETEROCICLIC ANTIDIABETIC COMPOUNDS - Google Patents
BRIDGED AND FUSED HETEROCICLIC ANTIDIABETIC COMPOUNDSInfo
- Publication number
- AR074965A1 AR074965A1 ARP100100146A ARP100100146A AR074965A1 AR 074965 A1 AR074965 A1 AR 074965A1 AR P100100146 A ARP100100146 A AR P100100146A AR P100100146 A ARP100100146 A AR P100100146A AR 074965 A1 AR074965 A1 AR 074965A1
- Authority
- AR
- Argentina
- Prior art keywords
- alkyl
- group
- cycloalkyl
- cycloalkylalkyl
- heterocycloalkyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title abstract 6
- 230000003178 anti-diabetic effect Effects 0.000 title 1
- 239000003472 antidiabetic agent Substances 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 abstract 27
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 25
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 abstract 20
- 229910052739 hydrogen Inorganic materials 0.000 abstract 17
- 125000003118 aryl group Chemical group 0.000 abstract 16
- 125000000592 heterocycloalkyl group Chemical group 0.000 abstract 16
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 15
- 125000001072 heteroaryl group Chemical group 0.000 abstract 15
- 125000004446 heteroarylalkyl group Chemical group 0.000 abstract 15
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 abstract 15
- 125000003545 alkoxy group Chemical group 0.000 abstract 10
- 125000005843 halogen group Chemical group 0.000 abstract 8
- 125000001188 haloalkyl group Chemical group 0.000 abstract 5
- 229910052736 halogen Inorganic materials 0.000 abstract 5
- 150000002367 halogens Chemical class 0.000 abstract 5
- 125000000000 cycloalkoxy group Chemical group 0.000 abstract 3
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 abstract 3
- 125000004438 haloalkoxy group Chemical group 0.000 abstract 3
- 229910052757 nitrogen Inorganic materials 0.000 abstract 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 abstract 2
- 102100026148 Free fatty acid receptor 1 Human genes 0.000 abstract 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 abstract 2
- 229910052760 oxygen Inorganic materials 0.000 abstract 2
- 230000002265 prevention Effects 0.000 abstract 2
- 229910052717 sulfur Inorganic materials 0.000 abstract 2
- -1 -S ( O) q-alkyl Chemical group 0.000 abstract 1
- 101710142060 Free fatty acid receptor 1 Proteins 0.000 abstract 1
- 108070000009 Free fatty acid receptors Proteins 0.000 abstract 1
- 101000912510 Homo sapiens Free fatty acid receptor 1 Proteins 0.000 abstract 1
- 102000004877 Insulin Human genes 0.000 abstract 1
- 108090001061 Insulin Proteins 0.000 abstract 1
- 206010022489 Insulin Resistance Diseases 0.000 abstract 1
- 241000124008 Mammalia Species 0.000 abstract 1
- 208000008589 Obesity Diseases 0.000 abstract 1
- 239000000556 agonist Substances 0.000 abstract 1
- 125000002947 alkylene group Chemical group 0.000 abstract 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 125000005842 heteroatom Chemical group 0.000 abstract 1
- 229940125396 insulin Drugs 0.000 abstract 1
- 150000002632 lipids Chemical class 0.000 abstract 1
- 235000020824 obesity Nutrition 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- 125000003831 tetrazolyl group Chemical group 0.000 abstract 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Emergency Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Los compuestos son agonistas del receptor 40 acoplado a la proteína G (GPR40, también conocido como receptor de ácido graso libre FFAR). Composiciones farmacéuticas que contienen estos compuestos, y al uso de estos compuestos para regular los niveles de insulina en un mamífero. Los compuestos pueden ser utilizados, por ejemplo en la prevención y tratamiento de la diabetes mellitus Tipo 2 y en la prevención y tratamiento de afecciones relacionadas con la diabetes mellitus Tipo 2, tal como la resistencia a la insulina, obesidad y trastornos lipídicos. Reivindicación 1: Un compuesto de la fórmula (1) o una sal aceptable para uso farmacéutico del mismo donde L es de la estructura de fórmula (2) ó (3); A es S(O)q, -[C(Ra)(Rb)]m-, o -C(O); D es un enlace, -S(O)q-[C(R12)(R13)]n-, -C(O)-[C(R12)(R13)]n-, -C(=NR9)-[C(R12)(R13)]n- o -[C(R12)(R13)]n-; E es un enlace, S(O)q, -C(O)-, o -[C(R12)(R13)]n-; F es -O-, -C(O)-, -S(O)q-, o -N(R9)-; W es -C- o -N-; X es un enlace, -O-, -O(O)-, -S(O)q, -C(Ra)(Rb)- o -N(R8)-; Y es un enlace, -[C(Ra)(Rb)]n-O-[C(Ra)(Rb)]n, -[C(Ra)(Rb)]n-C(O)-[C(Ra)(Rb)]n-, -[C(Ra)(Rb)]n-S(O)q-[C(Ra)(Rb)]n, -[C(Ra)(Rb)]m- o -N(R8)-; z está ausente, es un enlace, -[C(Ra)(Rb)]n-O-[C(Ra)(Rb)]n, -[C(Ra)(Rb)]n-C(O)-[C(Ra)(Rb)]n-, -[C(Ra)(Rb)]n-S(O)q-[C(Ra)(Rb)]n, -[C(Ra)(Rb)]m- o -N(R8)-; R es un grupo seleccionado del grupo formado por (i) un resto de fórmula (4); (ii) un resto de fórmula (5); (iii) un resto de fórmula (6); (iv) un resto de fórmula (7); y (v) tetrazolilo, donde Q es -CH-o -N-, y J es -S-, -CH2-, -O- o -N(R8)-; Ra se selecciona independientemente del grupo formado por H, -OH, halo, alcoxi, alquilo, cicloalquilo y cicloalquilalquilo; Rb se selecciona independientemente del grupo formado por H, -OH, halo, alcoxi, alquilo, cicloalquilo, y cicloalquilalquilo; R1 se selecciona del grupo formado por H, alquilo, cicloalquilo, cicloalquilalquilo, arilo, arilalquilo, heterocicloalquilo, heterocicloalquilalquilo, heteroarilo, heteroarilalquilo, -C(O)-R5, -C(O)O-R5, -S(O)q-R5, -C(O)N(R6)(R7), -C(O)-alquileno-OR4, -S(O)q-alquileno-OR4, -S(O)q-alquileno-N(R6)(R7), y -S(O)2N(R6)(R7); R2 se selecciona del grupo formado por H, alquilo, alcoxi, cicloalquilo, cicloalquiloxi, cicloalquilalquilo, y cicloalquilalcoxi, son opcionalmente sustituidos con uno o más grupos seleccionados de grupo formado por -OH, halo, alquilo, haloalquilo, alcoxi, haloalcoxi y cicloalquilo; R3 se selecciona independientemente del grupo formado por H, halógeno, -SF5, -S(O)q-alquilo, -CN, -NO2, -N(R6)(R7), -OH, alquilo, alcoxi, cicloalquilo, cicloalquiloxi, cicloalquilalquilo, y cicloalquilalcoxi donde dichos alquilo, alcoxi, cicloalquilo, cicloalquiloxi, cicloalquilalquilo, y cicloalquilalcoxi son opcionalmente sustituidos con uno o más (por ejemplo 1 a 5 o 1 a 3) grupos seleccionados del grupo formado por -OH, halo, -S(O)q-alquilo, alquilo, haloalquilo, alcoxi, haloalcoxi , y cicloalquilo; R4 se selecciona independientemente del grupo formado por H, alquilo, cicloalquilo, cicloalquilalquilo, arilo, arilalquilo, heterocicloalquilo, heterocicloalquilalquilo, heteroarilo, y heteroarilalquilo; R5 se selecciona independientemente del grupo formado por H, alquilo, cicloalquilo, cicloalquilalquilo, arilo, arilalquilo, heterocicloalquilo, heterocicloalquilalquilo, heteroarilo, y heteroarilalquilo; R6 se selecciona independientemente del grupo formado por H, alquilo, cicloalquilo, cicloalquilalquilo, arilo, arilalquilo, heterocicloalquilo, heterocicloalquilalquilo, heteroarilo y heteroarilalquilo; R7 se selecciona independientemente del grupo formado por H, alquilo, cicloalquilo, cicloalquilalquilo, arilo, arilalquilo, heterocicloalquilo, heterocicloalquilalquilo, heteroarilo, y heteroarilalquilo; o R6 y R7 en forma conjunta forman un anillo de heterocicloalquilo de 4 a 7 miembros o un anillo de heteroarilo de 5 ó 6 miembros que tiene opcionalmente, además del átomo de N, 1 ó 2 heteroátomos seleccionados del grupo formado por O, N(R8), N o S, donde dichos anillos son opcionalmente sustituidos con uno o más restos R16; R8 se selecciona independientemente del grupo formado por H, alquilo, cicloalquilo, cicloalquilalquilo, arilo, arilalquilo, heterocicloalquilo, heterocicloalquilalquilo, heteroarilo, heteroarilalquilo, -C(O)-R5, -C(O)O-R5, -C(O)N(R6)(R7), -C(O)-alquileno-OR4, -C(O)-alquileno-N(R6)(R7), -C(O)-alquileno-S(O)q-R5, -S(O)q-R5, -S(O)q-alquileno-OR4, -S(O)q-alquileno-N(R6)(R7), -alquileno-OR4, -alquileno-S(O)q-R5, -alquileno-N(R6)(R7), y -S(O)2N(R6)(R7) donde dichos alquilo, cicloalquilo, cicloalquilalquilo, arilo, arilalquilo, heterocicloalquilo, heterocicloalquilalquilo, heteroarilo, heteroarilalquilo y alquileno son opcionalmente sustituidos con uno o más grupos seleccionados del grupo formado por -OH, halo, alquilo, haloalquilo, alcoxi, haloalcoxi y cicloalquilo; R9 se selecciona independientemente del grupo formado por H, alquilo, haloalquilo; R10 se selecciona independientemente del grupo formado por H, -OH, alquilo, cicloalquilo o alcoxi donde dichos grupos alquilo, cicloalquilo o alcoxi son opcionalmente sustituidos con por lo menos un sustituyente seleccionado del grupo formado por halo y -OR5; R11 se selecciona independientemente del grupo formado por H, alquilo, y haloalquilo; R12 se selecciona independientemente del grupo formado por H, halógeno, -CN, -NO2, -N(R6)(R7), -OR4, alquilo, cicloalquilo, cicloalquilalquilo, arilo, arilalquilo, heterocicloalquilo, heterocicloalquilalquilo, heteroarilo y heteroarilalquilo; R13 se selecciona independientemente del grupo formado por H, halógeno, -CN, -NO2, -N(R6)(R7), -OR4, alquilo, cicloalquilo, cicloalquilalquilo, arilo, arilalquilo, heterocicloalquilo, heterocicloalquilalquilo, heteroarilo, y heteroarilalquilo; R14 se selecciona independientemente del grupo formado por H, halógeno, -CN, -NO2, -N(R6)(R7), -OR4, alquilo, cicloalquilo, cicloalquilalquilo, arilo, arilalquilo, heterocicloalquilo, heterocicloalquilalquilo, heteroarilo, y heteroarilalquilo; R15 se selecciona independientemente del grupo formado por H, halógeno, -CN, -NO2, -N(R6)(R7), -OR4, alquilo, cicloalquilo, cicloalquilalquilo, arilo, arilalquilo, heterocicloalquilo, heterocicloalquilalquilo, heteroarilo, y heteroarilalquilo, o R12 y R14 estén ausentes y R13 y R15 en forma conjunta forman un anillo arilo de 5 ó 6 miembros o un anillo heteroarilo de 5 ó 6 miembros, (“anillo B”) el cual tiene 1 ó 2 heteroátomos seleccionados del grupo formado por O, S o N, que está opcionalmente sustituido con uno o más grupos R16; donde cada uno de los grupos alquilo, cicloalquilo, cicloalquilalquilo, arilo, arilalquilo, heterocicloalquilo, heterocicloalquilalquilo, heteroarilo, y heteroarilalquilo en R1, R4, R5, R6, y R7 está independientemente no sustituido o sustituido con uno o más grupos R16, donde R16 se selecciona independientemente del grupo formado por alquilo, cicloalquilo, cicloalquilalquilo, arilo, arilalquilo, heterocicloalquilo, heterocicloalquilalquilo, heteroarilo, y heteroarilalquilo -OR4, -C(O)-R5, -C(O)O-R5, -S(O)qR5, -C(O)N(R6)(R7), y -S(O)2N(R6)(R7), -NO2, -SF5, -CN, -N(R6)(R7) y halo y donde cada grupo alquilo, cicloalquilo, cicloalquilalquilo, arilo, arilalquilo, heterocicloalquilo, heterocicloalquilalquilo, heteroarilo, y heteroarilalquilo en R16 está independientemente no sustituido o sustituido con uno o más grupos R17, donde R17 se selecciona independientemente del grupo formado por alquilo, cicloalquilo, cicloalquilalquilo, arilo, arilalquilo, heterocicloalquilo, heterocicloalquilalquilo, heteroarilo, heteroarilalquilo, -OR4, -C(O)-R5, -C(O)O-R5, -S(O)qR5, -C(O)N(R6)(R7), y -S(O)2N(R6)(R7), -NO2, -SF5, -CN, y halo; m es independientemente 1, 2 ó 3; n es independientemente 0, 1 ó 2; p es 0, 1, 2 ó 3; y q es independientemente 0, 1 ó 2, siempre que Y y Z no pueden ser un enlace al mismo tiempo.The compounds are agonists of the G-protein coupled receptor 40 (GPR40, also known as the FFAR free fatty acid receptor). Pharmaceutical compositions containing these compounds, and the use of these compounds to regulate insulin levels in a mammal. The compounds may be used, for example in the prevention and treatment of Type 2 diabetes mellitus and in the prevention and treatment of conditions related to Type 2 diabetes mellitus, such as insulin resistance, obesity and lipid disorders. Claim 1: A compound of the formula (1) or a salt acceptable for pharmaceutical use thereof wherein L is of the structure of formula (2) or (3); A is S (O) q, - [C (Ra) (Rb)] m-, or -C (O); D is a bond, -S (O) q- [C (R12) (R13)] n-, -C (O) - [C (R12) (R13)] n-, -C (= NR9) - [ C (R12) (R13)] n- or - [C (R12) (R13)] n-; E is a bond, S (O) q, -C (O) -, or - [C (R12) (R13)] n-; F is -O-, -C (O) -, -S (O) q-, or -N (R9) -; W is -C- or -N-; X is a bond, -O-, -O (O) -, -S (O) q, -C (Ra) (Rb) - or -N (R8) -; Y is a link, - [C (Ra) (Rb)] nO- [C (Ra) (Rb)] n, - [C (Ra) (Rb)] nC (O) - [C (Ra) (Rb )] n-, - [C (Ra) (Rb)] nS (O) q- [C (Ra) (Rb)] n, - [C (Ra) (Rb)] m- or -N (R8) -; z is absent, it is a link, - [C (Ra) (Rb)] nO- [C (Ra) (Rb)] n, - [C (Ra) (Rb)] nC (O) - [C (Ra ) (Rb)] n-, - [C (Ra) (Rb)] nS (O) q- [C (Ra) (Rb)] n, - [C (Ra) (Rb)] m- or -N (R8) -; R is a group selected from the group consisting of (i) a remainder of formula (4); (ii) a remainder of formula (5); (iii) a remainder of formula (6); (iv) a remainder of formula (7); and (v) tetrazolyl, where Q is -CH-or -N-, and J is -S-, -CH2-, -O- or -N (R8) -; Ra is independently selected from the group consisting of H, -OH, halo, alkoxy, alkyl, cycloalkyl and cycloalkylalkyl; Rb is independently selected from the group consisting of H, -OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; R1 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C (O) -R5, -C (O) O-R5, -S (O) q -R5, -C (O) N (R6) (R7), -C (O) -alkylene-OR4, -S (O) q-alkylene-OR4, -S (O) q-alkylene-N (R6) (R7), and -S (O) 2N (R6) (R7); R2 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy, are optionally substituted with one or more groups selected from the group consisting of -OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl; R3 is independently selected from the group consisting of H, halogen, -SF5, -S (O) q-alkyl, -CN, -NO2, -N (R6) (R7), -OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy are optionally substituted with one or more (for example 1 to 5 or 1 to 3) groups selected from the group consisting of -OH, halo, -S ( O) q-alkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; R4 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; R5 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; R6 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl; R7 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; or R6 and R7 together form a 4- to 7-membered heterocycloalkyl ring or a 5 or 6-membered heteroaryl ring which optionally has, in addition to the N, 1 or 2 heteroatom atom selected from the group consisting of O, N ( R8), N or S, wherein said rings are optionally substituted with one or more R16 moieties; R8 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C (O) -R5, -C (O) O-R5, -C (O) N (R6) (R7), -C (O) -alkylene-OR4, -C (O) -alkylene-N (R6) (R7), -C (O) -alkylene-S (O) q-R5, -S (O) q-R5, -S (O) q-alkylene-OR4, -S (O) q-alkylene-N (R6) (R7), -alkylene-OR4, -alkylene-S (O) q -R5, -alkylene-N (R6) (R7), and -S (O) 2N (R6) (R7) wherein said alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene are optionally substituted with one or more groups selected from the group consisting of -OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl; R9 is independently selected from the group consisting of H, alkyl, haloalkyl; R10 is independently selected from the group consisting of H, -OH, alkyl, cycloalkyl or alkoxy wherein said alkyl, cycloalkyl or alkoxy groups are optionally substituted with at least one substituent selected from the group consisting of halo and -OR5; R11 is independently selected from the group consisting of H, alkyl, and haloalkyl; R12 is independently selected from the group consisting of H, halogen, -CN, -NO2, -N (R6) (R7), -OR4, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl; R13 is independently selected from the group consisting of H, halogen, -CN, -NO2, -N (R6) (R7), -OR4, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; R14 is independently selected from the group consisting of H, halogen, -CN, -NO2, -N (R6) (R7), -OR4, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; R15 is independently selected from the group consisting of H, halogen, -CN, -NO2, -N (R6) (R7), -OR4, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, or R12 and R14 are absent and R13 and R15 together form a 5 or 6 membered aryl ring or a 5 or 6 membered heteroaryl ring, ("ring B") which has 1 or 2 heteroatoms selected from the group consisting of O , S or N, which is optionally substituted with one or more R16 groups; wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups at R1, R4, R5, R6, and R7 is independently unsubstituted or substituted with one or more R16 groups, where R16 is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl -OR4, -C (O) -R5, -C (O) O-R5, -S (O) qR5, -C (O) N (R6) (R7), and -S (O) 2N (R6) (R7), -NO2, -SF5, -CN, -N (R6) (R7) and halo and where each alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R16 is independently unsubstituted or substituted with one or more R17 groups, where R17 is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkyl alkyl, heteroaryl, heteroarylalkyl, -OR4, -C (O) -R5, -C (O) O-R5, -S (O) qR5, -C (O) N (R6) (R7), and -S ( O) 2N (R6) (R7), -NO2, -SF5, -CN, and halo; m is independently 1, 2 or 3; n is independently 0, 1 or 2; p is 0, 1, 2 or 3; and q is independently 0, 1 or 2, provided that Y and Z cannot be a link at the same time.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14687909P | 2009-01-23 | 2009-01-23 |
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| AR074965A1 true AR074965A1 (en) | 2011-02-23 |
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| ARP100100146A AR074965A1 (en) | 2009-01-23 | 2010-01-22 | BRIDGED AND FUSED HETEROCICLIC ANTIDIABETIC COMPOUNDS |
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| Country | Link |
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| US (1) | US20110312995A1 (en) |
| EP (1) | EP2389226B1 (en) |
| JP (1) | JP2012515781A (en) |
| AR (1) | AR074965A1 (en) |
| AU (1) | AU2010206786A1 (en) |
| CA (1) | CA2749930A1 (en) |
| TW (1) | TW201040172A (en) |
| WO (1) | WO2010085525A1 (en) |
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| AU2010206789A1 (en) | 2009-01-23 | 2011-07-28 | Merck Sharp & Dohme Corp. | Bridged and fused antidiabetic compounds |
| TW201040186A (en) | 2009-02-05 | 2010-11-16 | Schering Corp | Phthalazine-containing antidiabetic compounds |
| US8476287B2 (en) | 2009-12-25 | 2013-07-02 | Mochida Pharmaceutical Co., Ltd. | 3-hydroxy-5-arylisothiazole derivative |
| JP5809157B2 (en) | 2010-10-08 | 2015-11-10 | 持田製薬株式会社 | Cyclic amide derivative |
| US8557766B2 (en) | 2011-04-27 | 2013-10-15 | Mochida Pharmaceutical Co., Ltd. | 3-hydroxyisothiazole 1-oxide derivatives |
| AU2012248627A1 (en) | 2011-04-28 | 2013-11-14 | Mochida Pharmaceutical Co., Ltd. | Cyclic amide derivative |
| CN102731390A (en) * | 2012-07-07 | 2012-10-17 | 盛世泰科生物医药技术(苏州)有限公司 | Synthesis method of 6-bromo-2, 3-dihydro-1H-quinoline-4 ketone |
| CA2878625A1 (en) | 2012-07-11 | 2014-01-16 | Elcelyx Therapeutics, Inc. | Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk |
| US9527875B2 (en) | 2012-08-02 | 2016-12-27 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
| MX2015010935A (en) | 2013-02-22 | 2015-10-29 | Merck Sharp & Dohme | Antidiabetic bicyclic compounds. |
| WO2015051496A1 (en) | 2013-10-08 | 2015-04-16 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
| HK1221465A1 (en) | 2013-11-14 | 2017-06-02 | Cadila Healthcare Limited | Novel heterocyclic compounds |
| US10519115B2 (en) | 2013-11-15 | 2019-12-31 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
| EP3076959B1 (en) | 2013-12-04 | 2018-07-04 | Merck Sharp & Dohme Corp. | Antidiabetic bicyclic compounds |
| WO2015089809A1 (en) | 2013-12-19 | 2015-06-25 | Merck Sharp & Dohme Corp. | Antidiabetic substituted heteroaryl compounds |
| EP3102198B1 (en) | 2014-02-06 | 2020-08-26 | Merck Sharp & Dohme Corp. | Antidiabetic compounds |
| WO2015176267A1 (en) | 2014-05-22 | 2015-11-26 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
| US10100042B2 (en) | 2014-08-08 | 2018-10-16 | Merck Sharp & Dohme Corp. | [5,6]—fused bicyclic antidiabetic compounds |
| WO2016022448A1 (en) | 2014-08-08 | 2016-02-11 | Merck Sharp & Dohme Corp. | Antidiabetic bicyclic compounds |
| WO2016019587A1 (en) | 2014-08-08 | 2016-02-11 | Merck Sharp & Dohme Corp. | [7, 6]-fused bicyclic antidiabetic compounds |
| EP3177287B1 (en) | 2014-08-08 | 2022-02-23 | Merck Sharp & Dohme Corp. | Antidiabetic bicyclic compounds |
| US10676458B2 (en) | 2016-03-29 | 2020-06-09 | Merch Sharp & Dohne Corp. Rahway | Antidiabetic bicyclic compounds |
| EP3551176A4 (en) | 2016-12-06 | 2020-06-24 | Merck Sharp & Dohme Corp. | ANTIDIABETIC HETEROCYCLIC COMPOUNDS |
| WO2018118670A1 (en) | 2016-12-20 | 2018-06-28 | Merck Sharp & Dohme Corp. | Antidiabetic spirochroman compounds |
| US11225471B2 (en) | 2017-11-16 | 2022-01-18 | Merck Sharp & Dohme Corp. | Antidiabetic bicyclic compounds |
| CR20200347A (en) | 2018-02-13 | 2020-09-23 | Gilead Sciences Inc | Pd-1/pd-l1 inhibitors |
| US20210017174A1 (en) | 2018-03-07 | 2021-01-21 | Bayer Aktiengesellschaft | Identification and use of erk5 inhibitor |
| KR102591947B1 (en) | 2018-04-19 | 2023-10-25 | 길리애드 사이언시즈, 인코포레이티드 | PD-1/PD-L1 inhibitors |
| PT3820572T (en) | 2018-07-13 | 2023-11-10 | Gilead Sciences Inc | Pd-1/pd-l1 inhibitors |
| JP7158577B2 (en) | 2018-10-24 | 2022-10-21 | ギリアード サイエンシーズ， インコーポレイテッド | PD-1/PD-L1 inhibitor |
| PH12022550852A1 (en) | 2019-10-07 | 2023-05-03 | Kallyope Inc | Gpr119 agonists |
| CA3173731A1 (en) | 2020-02-28 | 2021-09-02 | Kallyope, Inc. | Gpr40 agonists |
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| WO1997028149A1 (en) | 1996-02-02 | 1997-08-07 | Merck & Co., Inc. | Method for raising hdl cholesterol levels |
| JP2004513076A (en) | 2000-07-25 | 2004-04-30 | メルク エンド カムパニー インコーポレーテッド | N-substituted indoles useful in the treatment of diabetes |
| RU2328483C2 (en) | 2002-08-29 | 2008-07-10 | Мерк Энд Ко., Инк. | Indoles with antidiabetic activity |
| US7714004B2 (en) * | 2002-12-20 | 2010-05-11 | Bayer Pharmaceuticals Corporation | Indane acetic acid derivatives and their use as pharmaceutical agents, intermediates, and method of preparation |
| US7737295B2 (en) | 2004-04-13 | 2010-06-15 | Merck Sharp & Dohme Corp. | CETP inhibitors |
| US20050245529A1 (en) | 2004-04-14 | 2005-11-03 | Boehringer Ingelheim International Gmbh | Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds |
| DOP2005000123A (en) | 2004-07-02 | 2011-07-15 | Merck Sharp & Dohme | CETP INHIBITORS |
| US20080090865A1 (en) | 2005-01-28 | 2008-04-17 | Min Ge | Antidiabetic Bicyclic Compounds |
| AU2006210954A1 (en) | 2005-01-31 | 2006-08-10 | Merck & Co., Inc. | Antidiabetic bicyclic compounds |
| MX2008011615A (en) * | 2006-03-14 | 2008-09-22 | Amgen Inc | Bicyclic carboxylic acid derivatives useful for treating metabolic disorders. |
| WO2007136572A2 (en) | 2006-05-15 | 2007-11-29 | Merck & Co., Inc. | Antidiabetic bicyclic compounds |
| WO2008054674A2 (en) | 2006-10-31 | 2008-05-08 | Merck & Co., Inc. | Antidiabetic bicyclic compounds |
-
2010
- 2010-01-21 WO PCT/US2010/021583 patent/WO2010085525A1/en not_active Ceased
- 2010-01-21 JP JP2011548086A patent/JP2012515781A/en not_active Withdrawn
- 2010-01-21 US US13/145,359 patent/US20110312995A1/en not_active Abandoned
- 2010-01-21 AU AU2010206786A patent/AU2010206786A1/en not_active Abandoned
- 2010-01-21 EP EP10703543.8A patent/EP2389226B1/en not_active Not-in-force
- 2010-01-21 CA CA2749930A patent/CA2749930A1/en not_active Abandoned
- 2010-01-22 AR ARP100100146A patent/AR074965A1/en not_active Application Discontinuation
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| Publication number | Publication date |
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| AU2010206786A1 (en) | 2011-07-28 |
| JP2012515781A (en) | 2012-07-12 |
| CA2749930A1 (en) | 2010-07-29 |
| WO2010085525A1 (en) | 2010-07-29 |
| TW201040172A (en) | 2010-11-16 |
| EP2389226A1 (en) | 2011-11-30 |
| US20110312995A1 (en) | 2011-12-22 |
| EP2389226B1 (en) | 2013-11-20 |
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